Quinazolinone copmpounds useful for the prophyloxis and treatment of diabetic complications

ABSTRACT

Novel quinazolinone compounds of the formula: ##STR1## wherein R is hydrogen atom or a lower alkyl, R 1  is a lower alkyl, a substituted or unsubstituted phenyl or an aralkyl, and R 2 , R 3 , R 4  and R 5  are the same or different and are each hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a lower alkoxycarbonyl or a lower alkoxycarbonyl-lower alkenyl, or two adjacent groups of R 2 ,R 3 , R 4  and R 5  when taken together form methylenedioxy and the other two are hydrogen atom, and a salt thereof, which are useful for the prophylaxis and treatment of various diabetic complications, and processes for the preparation thereof, and a pharmaceutical composition containing said compound as an active ingredient.

This invention relates to novel quinazolinone compounds and processesfor the preparation thereof. More particularly, it relates to novelquinazolinone compounds of the formula: ##STR2## wherein R is hydrogenatom or a lower alkyl, R¹ is a lower alkyl, a substituted orunsubstituted phenyl or an aralkyl, and R², R³, R⁴ and R⁵ are the sameor different and are each hydrogen atom, a halogen atom, a lower alkyl,a lower alkoxy, a lower alkoxycarbonyl or a lower alkoxycarbonyl-loweralkenyl, or two adjacent groups of R², R³, R⁴ and R⁵ when taken togetherform methylenedioxy and the other two are hydrogen atom, and a saltthereof, which are useful for the prophylaxis and treatment of variousdiabetic complications, and processes for the preparation thereof, andfurther a pharmaceutical composition containing said compound as anactive ingredient.

PRIOR ART

It is known that diabetic complications include diabetic neurosis,diabetic cataract, diabetic microangiopathy such as diabetic retinopathyand diabetic nephrosis, and the like and that these diabeticcomplications are induced by accumulation of polyols such as sorbitolwhich are converted from hexose etc. by aldose reductase in vivo [cf.The New England Journal of Medicine, Vol. 288, 831-836 (1973)]. In orderto prevent and treat the diabetic complications, there have hithertobeen proposed various aldose reductase inhibitors which can inhibit theaccumulation of polyols within the body, for instance, compounds havingchromane nucleus (cf. Japanese Pat. First Publication Nos. 53653/1978and 45185/1982, and U.S. Pat. No. 4,117,230), compounds havingthiazolidine nucleus (cf. Japanese Patent First Publication No.104876/1981), and compounds having phthalazine nucleus (cf. JapanesePatent First Publication No. 95582/1979).

Besides, there have been known some quinazolinone compounds, forinstance,3,1'-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione[cf. Chemie Berichte, Vol. 103, 2394 (1970)] and3,1',3'-trimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione[cf. Chemie Berichte, Vol. 110, 3849 (1977)], but there has never beenknown any pharmacological activity of these quinazolinone compounds.

BRIEF DESCRIPTION OF THE INVENTION

The present inventors have extensively studied variousspiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]compounds andpharmacological activities thereof and it has unexpectedly been foundthat the compounds of the formula (I) which have no substituent at 1'-and 3'- positions of knownspiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] compounds haveexcellent aldose reductase inhibitory activity.

An object of the invention is to provide novel qunazolinone compoundshaving excellent aldose reductase inhibitory activity and hence beinguseful for the prophylaxis and treatment of diabetic complications.Another object of the invention is to provide processes for thepreparation of said novel compounds. A further object of the inventionis to provide novel intermediates useful for the preparation of saidnovel quinazolinone compounds. A still further object of the inventionis to provide a pharmaceutical composition suitable for the prophylaxisand treatment of diabetic complications. These and other objects andadvantages of the invention will be apparent to persons skilled in theart from the following description.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention have the formula (I) as mentionedhereinbefore.

The substituents on the formula (I) denote the following groups.

The term "lower alkyl" denotes a straight chain or branched chain alkylhaving 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec.-butyl, tert.-butyl, or n-pentyl, isopentyl, etc.The term "lower alkoxy" denotes a straight chain or branched chainalkoxy having 1 to 5 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, n-pentyloxy,isopentyloxy, etc. The term "substituted or unsubstituted phenyl"denotes a phenyl or a phenyl substituted by a member selected from thegroup consisting of a lower alkyl and a halogen atom, such as analkylphenyl having 1 to 5 carbon atoms in the alkyl moiety (e.g.methylphenyl, ethylphenyl, n-propylphenyl, isopropylphenyl,n-butylphenyl, n-pentylphenyl, etc.) and a halogenophenyl (e.g.chlorophenyl, fluorophenyl, bromophenyl). The term "aralkyl" denotes aphenylalkyl having 1 to 3 carbon atoms in the alkyl moiety, such asbenzyl, phenethyl, etc. The term "halogen atom" denotes fluorine,chlorine, or bromine. The term "lower alkoxycarbonyl" denotes a straightchain or branched chain alkoxycarbonyl having 2 to 6 carbon atoms, suchas methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl, n-pentyloxycarbonyl, etc. The term"lower alkoxycarbonyl-lower alkenyl" denotes a straight chain orbranched chain alkenyl having 2 to 6 carbon atoms which is substitutedby the lower alkoxycarbonyl as set forth above, such asmethoxycarbonylvinyl, ethoxycarbonylvinyl, n-propoxycarbonylvinyl,isopropoxycarbonylvinyl, n-butoxycarbonylvinyl,n-pentyloxycarbonylvinyl, etc.

Preferred groups for the substituents in the formula (I) are hydrogenand C₁₋₄ alkyl for R; C₁₋₄ alkyl, phenyl, C₁₋₄ alkyl-phenyl,halogenophenyl and phenyl-C₁₋₂ alkyl for R¹ ; and hydrogen, halogen,C₁₋₄ alkyl, C₂₋₅ alkoxycarbonyl, and C₂₋₅ alkoxycarbonyl-C₁₋₄ alkenylfor each R², R³, R⁴ and R⁵, or methylenedioxy formed by adjacent twogroups of R², R³, R⁴ and R⁵.

Preferred compounds of the invention are compounds of the formula (I)wherein R is hydrogen or C₁₋₄ alkyl: R¹ is C₁₋₄ alkyl, phenyl, C₁₋₄alkyl-phenyl, halogenophenyl, or phenyl-C₁₋₂ alkyl; and R², R³, R⁴ andR⁵ are the same or different and are each hydrogen, halogen, C₁₋₄ alkyl,C₂₋₅ alkoxycarbonyl, or C₂₋₅ alkoxycarbonyl-C₂₋₄ alkenyl, or twoadjacent groups of R², R³, R⁴ and R⁵ when taken together formmethylenedioxy and the other two are hydrogen.

Further preferred compounds of the invention are compounds of theformula (I) wherein R is hydrogen or C₁₋₄ alkyl; R¹ is C₁₋₄ alkyl,phenyl, C₁₋₄ alkyl-phenyl, halogenophenyl, or phenyl-C₁₋₂ alkyl; R² ishydrogen, halogen or C₁₋₄ alkyl; R³ and R⁴ are the same or different andare each hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₂₋₅alkoxycarbonyl, or C₂₋₅ alkoxycarbonyl-C₂₋₄ alkenyl, or R³ and R⁴ whentaken together form methylenedioxy; and R⁵ is hydrogen or halogen.

Still further preferred compounds of the invention are compounds of theformula (I) wherein R is hydrogen, methyl or isobutyl R¹ is methyl,n-butyl, phenyl, methylphenyl, chlorophenyl, or benzyl R² is hydrogen,chlorine or methyl; R³ and R⁴ are the same or different and are eachhydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxycarbonyl,or ethoxycarbonylvinyl, or R³ and R⁴ when taken together formmethylenedioxy and R⁵ is hydrogen, fluorine or chlorine.

Particularly preferred compounds of the invention are compounds of theformula (I) wherein R is hydrogen or isobutyl; R¹ is methyl, n-butyl,phenyl, methylphenyl, chlorophenyl, or benzyl; R² is hydrogen or methylR³ is hydrogen, fluorine, chlorine, bromine, methyl or ethoxycarbonyl;R⁴ is hydrogen, fluorine, chlorine, methyl or methoxy, or R³ and R⁴ whentaken together form methylenedioxy; and R⁵ is hydrogen, fluorine orchlorine.

In other preferred embodiment, R is hydrogen or C₁₋₄ alkyl; R¹ is C₁₋₄alkyl; R² is hydrogen; R³ is halogen; R⁴ is hydrogen, halogen or C₁₋₄alkyl; and R⁵ is hydrogen or halogen. Particularly, R is hydrogen orisobutyl; R¹ is methyl; R² is hydrogen; R³ is fluorine, chlorine orbromine; R⁴ is hydrogen, chlorine or methyl; and R⁵ is hydrogen orchlorine.

The compounds (I) of the invention have an asymmetric carbon in themolecule and hence may include two optical isomers. The presentinvention includes these optical isomers and racemic mixture thereof.

The compounds (I) of the invention can be prepared by various processes.For example, The compound (I) in which R is hydrogen atom can beprepared by subjecting the following compounds to cyclization reaction.##STR3## wherein R⁶ is a lower alkyl, and R², R³, R⁴ and R⁵ are the sameas above.

The cyclization reaction of the compound (II) or the compound (III) canbe carried out in an appropriate solvent at an elevated temperature. Thecyclization of the compound (II) is preferably carried out in thepresence of an acid (e.g. hydrochloric acid, hydrobromic acid, formicacid, etc.) at a temperature of 20° to 100° C., more preferably 60° to90° C. The cyclization of the compound (III) is preferably carried outat a temperature of 150° to 250° C., more preferably 180° to 200° C. Thesolvent used in the cyclization of the compound (II) includes water,methanol, ethanol, dimethylformamide, 1,2-dichlorobenzene, and the like.The solvent used in the cyclization of the compound (III) includes1,2-dichlorobenzene, nitrobenzene, naphthalene, biphenyl, and the like.

Alternatively, compounds of the formula: ##STR4## wherein R³¹ is ahalogen atom, R⁴¹ is hydrogen atom or a lower alkoxy, R⁵¹ is hydrogenatom or a halogen atom, and R and R¹ are the same as above, can beprepared by treating a compound of the formula: ##STR5## wherein R, R¹and R⁴¹ are the same as above, or a salt thereof with a halogenatingagent.

The starting compound (I-b) may be used for the reaction in the form ofa free base or of a salt thereof for instance, an alkali metal salt(e.g. sodium salt, potassium salt).

The treatment of the compound (I-b) with a halogenating agent can becarried out in an appropriate solvent. The halogenating agent includessulfuryl chloride, chlorine, bromine, iodobenzene dichloride,N-bromosuccinimide, and the like. The solvent includes acetic acid,tetrahydrofuran, dioxane, water, or a mixture thereof. The reaction ispreferably carried out at a temperature of 0° to 100° C., morepreferably 20° to 70° C.

Besides, compounds of the formula: ##STR6## wherein R' is a lower alkyl,R¹, R², R³, R⁴ and R⁵ are the same as above, can be prepared by reactinga compound of the formula: ##STR7## wherein X¹ and X² are a protectinggroup, and R¹, R², R³, R⁴ and R⁵ are the same as above, with analkylating agent, such as a lower alkyl halide, and removing theprotecting group, optionally followed by converting the resulting freebase into a salt thereof.

In the starting compound (IV), the protecting groups X¹ and X² includeany conventional protecting groups suitable for protecting an amino orimino group, for example, acetyl, benzyloxymethyl, benzoyl,benzyloxycarbonyl, tetrahydrofuranyl, and the like.

The alkylation of the compound (IV) with the lower alkyl halide ispreferably carried out in an appropriate solvent in the presence of abase, such as sodium hydride, sodium hydroxide, potassium hydroxide,potassium carbonate, and the like. The solvent includesdimethylformamide, tetrahydrofuran, acetone, dimethylsulfoxide, and thelike. The reaction is preferably carried out at a temperature of -20° to100° C.

The removal of the protecting group can be carried out by a conventionalmethod suitable for each kind of the protecting groups, for example, byhydrolysis, electrolytic reduction, treatment with a base, treatmentwith an acid, catalytic reduction, oxidation and the like. Theconversion of a free base into a salt can be carried out by aconventional method.

When the compounds (I) are obtained in the form of a racemic mixture,they can be resolved into each optical isomer by a conventional method.For instance, the optical resolution can be carried out by reacting theracemic mixture of the compounds (I) with a resolving agent in anappropriate solvent, isolating a hardly soluble diastereomeric salt inthe form of a crystal and then isolating the soluble diastereomeric saltfrom the mother liquid by utilizing the difference in the solubility ofthe two diastereomeric salts. The resolving agent includes, for example,natural origin products such as brucine, quinine, cinchonidine,N-n-octylglucamine, dehydroabietylamine, etc., and optically activecompounds such as α-methylbenzylamine, lysine, phenylalaninamide,tyrosine hydrazide, etc. The solvent includes methanol, ethanol,isopropanol, dioxane, tetrahydrofuran, water, or a mixture thereof. Thediastereomeric salts thus prepared can be converted to the desiredoptically active compounds (I), for example, by treating with an acid(e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid,etc.).

The starting compounds (II) and (III) used in the above reaction arealso novel compounds. The compound (II) can be prepared, for example, byreacting a compound of the formula: ##STR8## wherein R², R³, R⁴ and R⁵are the same as above, or a salt thereof (e.g. sodium salt, potassiumsalt, etc.) with a compound of the formula:

    R.sup.1 NC═O                                           (VI)

wherein R¹ is the same as above, in a suitable solvent (e.g.dimethylacetamide, dimethylformamide, etc.) in the presence of a base(e.g. triethylamine, etc.) at a temperature of -20° to 50° C. to give acompound of the formula: ##STR9## wherein R¹, R², R³, R⁴ and R⁵ are thesame as above, and then reacting the compound (VII) obtained above witha compound of the formula: ##STR10## wherein R⁶ is the same as above, ora salt thereof (e.g. hydrobromide, hydroiodide, sulfate, etc.) in asuitable solvent (e.g. tetrahydrofuran, etc.) in the presence of a base(e.g. triethylamine, etc.) at a temperature of 0° to 100° C.

The compound (II) can also be prepared by reacting the compound (VII)with thiourea in a suitable solvent (e.g. tetrahydrofuran, etc.) in thepresence of a base (e.g. triethylamine, etc.) at a temperature of 0° to100° C. to give a compound of the formula: ##STR11## wherein R¹, R², R³,R⁴ and R⁵ are the same as defined above, and then reacting the compound(IX) obtained above with a compound of the formula:

    R.sup.6 X                                                  (X)

wherein X is a halogen atom, and R⁶ is the same as above, in a suitablesolvent (e.g. dimethylformamide, etc.) in the presence of a base (e.g.sodium hydride, etc.) at a temperature of 0° to 50° C.

Besides, the compound (III) can be prepared, for example, by reactingthe compound (VII) or a salt thereof with urea in a suitable solvent(e.g. tetrahydrofuran, etc.) in the presence of a base (e.g.1,8-diazabicyclo[5.4.0]-7-undecene, etc.) at a temperature of 20° to100° C.

The compounds (II) and (III) thus prepared can be used for the processesof the invention as they stands or after being purified by aconventional method.

The compounds (I) of the invention can be used as a medicament in theform of a free base or a pharmaceutically acceptable salt thereof. Thepharmaceutically acceptable salt includes, for example, sodium salt,potassium salt, calcium salt, lysine salt, ethylenediamine salt,diethanolamine salt, and the like. These salts can easily be prepared bytreating the free base of the compounds (I) with a base by aconventional method.

The compounds (I) and salts thereof have excellent aldose reductaseinhibitory activity and hence are useful for the prophylaxis andtreatment of various chronic symptoms associated with diabetes, i.e.diabetic complications, in warm-blooded animals, for example, diabeticneurosis, diabetic cataract, and diabetic microangiopathy such asdiabetic retinopathy and diabetic nephrosis. The compounds (I) and saltsthereof of the invention have also advantages that they have lowtoxicity and less neurotoxic side effects (e.g. dysbasia, areflexia,astasia, blepharoptosis, etc.).

The compounds (I) and salts thereof of the invention can be administeredorally or parenterally. They can be administered in conventionalpharmaceutical preparations, for example, tablets, granules, finegranules, powders, capsules, injections, eye drugs (e.g. eyewash, eyeointment, etc.), and the like. These preparations can be prepared byadmixing the active compound (I) or salt thereof with conventionalpharmaceutically acceptable carriers or diluents. The pharmaceuticallyacceptable carriers or diluents include excipients (e.g. sucrose,starches, mannitol, glucose, cellulose, talc, calcium phosphate, etc.),binding agents (e.g. methylcellulose, gelatin, gum arabic, polyethyleneglycol, etc.), disintegrators (e.g. starches, carboxymethyl cellulose,sodium hydrogen carbonate, calcium phosphate, etc.), lubricants (e.g.magnesium stearate, talc, sodium laurylsulfate, etc.), preservatives(e.g. sodium benzoate, sodium hydrogen sulfide, etc.), stabilizers (e.g.citric acid, sodium citrate, etc.), and the like.

The dose of the compounds (I) and the pharmaceutically acceptable saltsthereof may vary depending on the administration routes, ages, weightand states of the patients, severity of diseases, and the like, but isusually in the range of about 0.01 to 200 mg/kg/day, preferably 0.1 to50 mg/kg/day.

The pharmacological activities of the compounds (I) and the saltsthereof are illustrated by the following experiments.

EXPERIMENT 1 Aldose reductase inhibitory activity

Method:

Aldose reductase was obtained from lens of male rabbit (weighing 2.5-3.5kg) in the same manner as described in J. Biol. Chem., Vol. 240, 877-882(1965). The inhibitory activity of the test compounds against the aldosereductase was measured in the same manner as described in Biochim.Biophys. Acta., Vol. 128, 474-482 (1966). The aldose reductaseinhibitory activity of the test compounds was shown by a concentrationof the test compounds which was required for 50% inhibition of aldosereductase activity (i.e. 50% inhibitory concentration: IC₅₀).

    ______________________________________                                        Test compounds:                                                               No.   Compound name                                                           ______________________________________                                        (Compounds of the invention)                                                  1.    6-Chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-                        4,4'-imidazolidine]-2,2',5'-trione                                      2.    d-6-Chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazol-                         ine-4,4'-imidazolidine]-2,2',5'-trione                                  3.    6-Chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-                        4,4'-imidazolidine]-2,2',5'-trione-1'-sodium salt                       4.    d-6-fluoro-3-methyl-spiro[1,2,3,4-tetrahydroquinazol-                         ine-4,4'-imidazolidine]-2,2',5'-trione                                  5.    6-Chloro-3,7-dimethyl-spiro[1,2,3,4-tetrahydro-                               quinazoline-4,4'-imidazolidine]-2,2',5'-trione                          6.    6-Bromo-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-                         4,4'-imidazolidine]-2,2',5'-trione                                      7.    6,7-Dichloro-3-methyl-spiro[1,2,3,4-tetrahydro-                               quinazoline-4,4'-imidazolidine]-2,2',5'-trione                          8.    6,8-Dichloro-3-methyl-spiro[1,2,3,4-tetrahydro-                               quinazoline-4,4'-imidazolidine]-2,2',5'-trione                          9.    6-Fluoro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-                        4,4'-imidazolidine]-2,2',5'-trione                                      10.   1-Isobutyl-6-chloro-3-methyl-spiro[1,2,3,4-tetrahydro-                        quinazoline-4,4'-imidazolidine]-2,2',5'-trione                          (Reference compounds)                                                         11.   3,1'-Dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-                            4,4'-imidazolidine]-2,2',5'-trione [disclosed in                              Chem. Ber., 103, 2394 (1970)]                                           12.   3,1',3'-Trimethyl-spiro[1,2,3,4-tetrahydroquinazoline-                        4,4'-imidazolidine]-2,2',5'-trione [disclosed in Chem.                        Ber., 110, 3849 (1977)]                                                 ______________________________________                                    

Results:

The results are shown in Table 1.

    ______________________________________                                                      Aldose reductase inhibitory activity                            Test Compd. No.                                                                             IC.sub.50 (M)                                                   ______________________________________                                        Compounds of the                                                              invention:                                                                    1             5.6 × 10.sup.-8                                           2             2.2 × 10.sup.-8                                           3             2.9 × 10.sup.-8                                           4             6.4 × 10.sup.-8                                           5             3.0 × 10.sup.-8                                           6             5.2 × 10.sup.-8                                           7             7.4 × 10.sup.-8                                           8             3.7 × 10.sup.-8                                           9             1.0 × 10.sup.-7                                           10            2.7 × 10.sup.-7                                           Reference compounds                                                           11            1.0 × 10.sup.-5                                           12            >5 × 10.sup.-5                                            ______________________________________                                    

EXPERIMENT 2 Inhibitory activity of accumulation of polyols

Method:

Slc:Wistar male rats (3-4 weeks old, one group: 3 rats) were fed with(i) a 20% galactose-added diet containing 20 mg % of a test compound(i.e. the test compound being contained in an amount of 20 mg per 100 gof the diet) (test compound-administered group), (ii) a 20%galactose-added diet (galactose control group), and (iii) a normal diet(no galactose) (normal control group) for 6 days. After the feeding, therats were killed by cutting the carotid artery under ether anesthesia,and immediately, the sciatic nerves at both sides were taken out, andthe amount of polyols accumulated in the sciatic nerves was measured byan acetyl-acetone method as described in Science, Vol. 182, 1146-1148(1973). The polyol accumulation inhibition rate was calculated by thefollowing equation. ##EQU1##

Results:

As a result, the compounds of the invention used in Experiment 1 (i.e.Test Compound Nos. 1-10) showed all more than 50% of polyol accumulationinhibition rate.

EXPERIMENT 3 Acute toxicity and observation of symptoms

A suspension of the test compound in 0.5% carboxymethyl cellulose wasorally administered to ddY male mice (weighing about 25 g, one group: 3mice), and gross behavior and symptoms of the mice were observed for 14days. As a result, in the mice administered with the compounds of theinvention: d- anddl-6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trioneno mouse died, and there was not observed any abnormal symptom such asdysbasia, areflexia, astasia, blepharoptosis, dyspnea, skin flush,lacrimation, etc.

The compounds (I) and their salts of the invention and preparationthereof are illustrated by the following Examples and Preparations.

EXAMPLE 1

5-Chloro-1-methylcarbamoylisatin (4.0 g) is dissolved in tetrahydrofuran(40 ml) and thereto are added 2-ethylisothiourea hydrobromide (4.0 g)and triethylamine (3.0 ml), and the mixture is stirred at roomtemperature for one hour. The reaction mixture is concentrated underreduced pressure to remove the solvent. To the residue [i.e. 6-chloro-3-methyl-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline]is added 10% hydrochloric acid (50 ml), and the mixture is stirred at70°-80° C. for 3 hours. After cooling, the precipitates are taken byfiltration to give6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(2.5 g, yield 53.1%).

M.p.>280° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3300, 1780, 1740, 1718

MS (m/e): 280 (M⁺)

NMR (DMSO-d₆) δ: 2.80 (3H, s), 6.92 (1H, d, J=9 Hz), 7.06 (1H, d, J=2Hz), 7.40 (1H, d, d, J=9 Hz, J=2 Hz), 9.11 (1H, s), 10.07 (1H, s), 11.40(1H, s)

EXAMPLES 2 to 22

In the same manner as described in Example 1, the corresponding startingcompounds are treated to give the compounds as shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR12##                                                                     ##STR13##                                                                    __________________________________________________________________________    [I] (R.sup.1 = CH.sub.3, R.sup.5 = H)                                                           Physical properties, etc.                                   Ex.                                                                              Compound (I)   Yield                                                                              MS                                                     No.                                                                              R.sup.2                                                                          R.sup.3 R.sup.4                                                                           & M.p.                                                                             (m/e)                                                                              IR ν.sub.max.sup.nujol (cm.sup.-1)                                                   NMR (DMSOd.sub.6)                       __________________________________________________________________________                                          δ:                                 2 H  F       H   >280° C.                                                                    264(M.sup.+)                                                                       3280, 3190, 1783,                                                                       2.78 (3H, s), 6.67-7.35 (3H, m),                                              9.03                                                                1735, 1657, 1610                                                                        (1H, s), 9.90 (1H, s), 11.31 (1H,                                             s)                                       3 Cl H       "   >280° C.                                                                    280(M.sup.+)                                                                       3300, 2900, 1780,                                                                       2.82 (3H, s), 6.87-7.40 (3H, m),                                              9.00                                                                1740, 1720, 1640                                                                        (1H, s), 10.20 (1H, s), 11.40 (1H,                                            s)                                       4 H  "       Cl  75%  280(M.sup.+)                                                                       3200, 2900, 1770,                                                                       2.82 (3H, s), 6.90-7.30 (3H, m),                                              9.10                                                      >280° C.                                                                         1740, 1725, 1670                                                                        (1H, s), 10.08 (1H, s), 11.30 (1H,                                            s)                                       5 "  CH.sub.3 O                                                                            H   270- 276(M.sup.+)   2.80 (3H, s), 3.77 (3H, s), 6.50                                              (1H,                                                      272° C.      d, J=2 Hz), 6.67 (1H, d, d, J=9                                               Hz,                                                                           J=2 Hz), 7.08 (1H, d, J=9 Hz),                                                9.10                                                                          (1H, s), 10.00 (1H, s), 11.45 (1H,                                            s)                                       6 H  CH.sub.3                                                                              H   57.4%                                                                              260(M.sup.+)                                                                       3200, 1800, 1720,                                                                       2.20 (3H, s), 2.79 (3H, s),                                                   6.60-7.20                                                 >280° C.                                                                         1650, 1610                                                                              (3H, m), 8.94 (1H, s), 9.72 (1H,                                              s),                                                                           11.20 (1H, s)                            7 "  OCH.sub.2 O >280° C.                                                                    290(M.sup.+)                                                                       3400, 3180, 3070,                                                                       2.76 (3H, s), 6.01 (2H, d, J=2                                                Hz),                                                                1789, 1715, 1680,                                                                       6.45 (1H, s), 6.54 (1H, s), 9.00                                              (1H,                                                                1642      s), 9.74 (1H, s), 11.30 (1H, s)           8                                                                              "  Cl      CH.sub.3                                                                          50.1%                                                                              294(M.sup.+)                                                                       3250, 3100, 1780,                                                                       2.30 (3H, s), 2.80 (3H, s), 6.93                                              (1H,                                                      >280° C.                                                                         1730, 1660, 1600                                                                        s), 7.10 (1H, s), 9.20 (1H, s),                                               10.11                                                                         (1H, s), 11.49 (1H, s)                   9 "  H       CH.sub.3 O                                                                        270- 276(M.sup.+)   2.80 (3H, s), 3.77 (3H, s), 6.50                                              (1H,                                                      272° C.      d, J=2 Hz), 6.67 (1H, d, d, J=9                                               Hz,                                                                           J=2 Hz), 7.08 (1H, d, J=9 Hz),                                                9.10                                                                          (1H, s), 10.00 (1H, s), 11.45 (1H,                                            s)                                      10 "  "       CH.sub.3                                                                          65%  260(M.sup.+)                                                                       3270, 1780, 1730,                                                                       2.21 (3H, s), 2.72 (3H, s),                                                   6.60-7.00                                                 >280° C.                                                                         1660, 1604                                                                              (3H, m), 8.90 (1H, s), 9.76 (1H,                                              s),                                                                           11.15 (1H, s)                           __________________________________________________________________________    [II] (R.sup.1 = CH.sub. 3, R.sup.2 = H)                                                         Physical properties, etc.                                   Ex.                                                                              Compound (I)   Yield                                                                              MS                                                     No.                                                                              R.sup.3                                                                          R.sup.4 R.sup.5                                                                           & M.p.                                                                             (m/e)                                                                              IR ν.sub.max.sup.nujol (cm.sup.-1)                                                   NMR (DMSOd.sub.6)                       __________________________________________________________________________                                          δ:                                11 F  F       F   55.3%     3250, 3150, 3020,                                                                       2.80 (3H, s), 7.07-7.40 (1H, m),                                              9.15                                                      >280° C.                                                                         1800, 1720                                                                              (1H, s), 10.35 (1H, s), 11.45 (1H,                                            br)                                     12 H  H       F   50.2%                                                                              264(M.sup.+)                                                                       3300, 3200, 3050,                                                                       2.80 (3H, s), 6.70-7.40 (3H, m),                                              9.12                                                      >280° C.                                                                         1800, 1750, 1710                                                                        (1H, s), 10.00 (1H, s), 11.38 (1H,                                            s)                                      __________________________________________________________________________    [III] (R.sup.1 = CH.sub.3, R.sup.5 = H)                                                         Physical properties, etc.                                   Ex.                                                                              Compound (I)   Yield                                                                              MS                                                     No.                                                                              R.sup.2                                                                          R.sup.3 R.sup.4                                                                           & M.p.                                                                             (m/e)                                                                              IR ν.sub.max.sup.nujol (cm.sup.-1)                                                   NMR (DMSOd.sub.6)                       __________________________________________________________________________                                          δ:                                13 H  Br      H   50.4%                                                                              324(M.sup.30 )                                                                     3250, 3100, 1775,                                                                       2.79 (3H, s), 6.87 (1H, d, J=8 Hz)                        >280° C.                                                                         1730, 1650, 1600                                                                        7.15 (1H, d, J=2 Hz), 7.50 (1H, d,                                            d, J=8 Hz, J=2 Hz), 9.12 (1H, s),                                             10.09 (1H, s), 11.50 (1H, br)           14 CH.sub.3                                                                         H       "   >280° C.                                                                    260(M.sup.+)                                                                       3300, 2720, 1742,                                                                       2.17 (3H, s), 2.80 (3H, s), 6.6-                                    1720, 1660, 1612                                                                        7.0 (2H, m), 7.1-7.5 (1H, m), 8.98                                            (1H, s)                                 15 H  Cl      CH.sub.3 O                                                                        55%  310(M.sup.+)   2.74 (3H, s), 3.80 (3H, s), 6.58                          >280° C.     (1H, s), 6.98 (1H, s), 8.99 (1H,                                              s)                                                                            9.90 (1H, s), 11.20 (1H, s)             16 "  COOC.sub.2 H.sub.5                                                                    H   55.3%                                                                              318(M.sup.+)                                                                       3250, 1795, 1730,                                                                       1.27 (3H, t, J=7 Hz), 2.78 (3H,                                               s),                                                       >280° C.                                                                         1690, 1616                                                                              4.25 (2H, q, J=7 Hz), 6.93 (1H, d,                                            J=9 Hz), 7.4-8.1 (2H, m), 9.09                                                (1H,                                                                          s), 10.26 (1H, s), 11.33 (1H, s)        17 "  CHCH    "   >280° C.                                                                    344(M.sup.+)                                                                       1795, 1740, 1678,                                                                       1.23 (3H, t, J=7 Hz), 2.76 (3H,                                               s),                                           COOC.sub.2 H.sub.5    1658, 1615, 1603                                                                        4.13 (2H, q, J=7 Hz), 6.41 (1H, d,                                            J=17 Hz), 6.84 (1H, d, J=9 Hz),                                               7.3-7.9 (2H, m), 7.56 (1H, d, J=17                                            Hz), 8.96 (1H, s), 10.07 (1H, s),                                             10.9-11.5 (1H, br)                      __________________________________________________________________________    [IV] (R.sup.2 -R.sup.5 = H)                                                                     Physical properties, etc.                                   Ex.                                                                              Compound (I)   Yield                                                                              MS                                                     No.                                                                              R.sup.1        & M.p.                                                                             (m/e)                                                                              IR ν.sub.max.sup.nujol (cm.sup.-1)                                                   NMR (DMSOd.sub.6 δ:               __________________________________________________________________________    18 CH.sub.3 (CH.sub.2).sub.3                                                                    263- 288(M.sup.+)                                                                       3240, 1782, 1770,                                                                       0.7-1.9 (7H, m), 2.7-3.8 (2H, m),                         266° C.                                                                          1725, 1665, 1613                                                                        6.7-7.4 (4H, m), 9.05 (1H, s),                                                9.77                                                                          (1H, s), 11.14 (1H, s)                  19                                                                                ##STR14##          308(M.sup.+)                                                                       3400, 3050, 1785, 1738, 1660,                                                           6.64-7.50 (9H, m), 9.10 (1H, s),                                              10.05 (1H, s), 10.80 (1H, br s)         20                                                                                ##STR15##     >280° C.                                                                    322(M.sup.+)                                                                       3240, 3050, 1782, 1738, 1720                                                            4.50 (2H, ABq, J=24 Hz, 16 Hz),                                               6.87-7.50 (9H, m), 9.13 (1H, s),                                              9.97 1H, s), 11,18 (1H,                 __________________________________________________________________________                                          s)                                  

EXAMPLE 21

3-Methyl-4-hydroxy-4-(2-ethylisothioureidocarbonyl)-2-oxo-1,2,3,4-tetrahydroquinazoline(2.0 g) is suspended in 10% hydrochloric acid (20 ml), and the mixtureis stirred at 70°-80° C. for 3 hours. After cooling, the precipitatesare taken by filtration and recrystallized from dimethylsulfoxide togive3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(1.2 g).

M.p.>280° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3300, 3120, 3080, 1781, 1735, 1680, 1615

MS (m/e): 246 (M⁺)

NMR (DMSO-d₆) δ: 2.80 (3H, s), 6.70-7.50 (4H, m), 9.05 (1H, s), 9.91(1H, s), 11.31 (1H, s)

EXAMPLES 22 to 23

In the same manner as described in Example 21, the correspondingstarting materials are treated to give the following compounds.

(22)3-(4-Methylphenyl)-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione-1/2HCON(CH₃)₂

M.p. 213°-215° C. (recrystallized from dimethylformamide-water)

IR ν_(max) ^(nujol) (cm⁻¹): 1780, 1740, 1670, 1608

MS (m/e): 322 (M⁺)

NMR (DMSO-d₆) δ: 2.32 (3H, s), 2.80 (3H, d, J=11 Hz), 6.80-7.60 (8H, m),9.20 (1H, s), 10.08 (1H, s), 10.86 (1H, s)

(23)3-(4-Chlorophenyl)-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione.1/2 HCON(CH₃)₂

Yield: 82.7%

M.p.>280° C.

IR ν_(max) ^(nujol) (cm⁻¹): 1788, 1740, 1662, 1610

MS (m/e): 342 (M⁺)

NMR (DMSO-d₆) δ: 2.80 (3H, d, J=11 Hz), 6.90-7.70 (8H, m), 9.60 (1H, s),10.20 (1H, s), 11.70 (1H, s)

EXAMPLE 24

(1) 5,6-Dichloro-1-methylcarbamoylisatin (9.6 g) is suspended intetrahydrofuran (100 ml) and thereto are added thiourea (3.0 g) andtriethylamine (5.6 ml), and the mixture is stirred at room temperaturefor 5 hours. The resulting precipitates are taken by filtration to give6,7-dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline(4.1 g). M.p. 225-228° C.

(2)6,7-Dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline(2.8 g) is dissolved in dimethylformamide (30 ml), and thereto is addedsodium hydride (60% oily suspension) (0.32 g), and the mixture isstirred at room temperature for 30 minutes. To the mixture is addedethyl bromide (2 ml), and the mixture is further stirred for 30 minutes,and then the solvent is distilled off under reduced pressure. To theresidue [i.e.6,7-dichloro-3-methyl-4-hydroxy-4-(2-methylisothioureido)-carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline]is added 10% hydrochloric acid (30 ml), and the mixture is stirred at70° C. for 4 hours. After cooling, the precipitates are taken byfiltration, washed with 10% aqueous sodium hydrogen carbonate solutionand then recrystallized from dimethylformamide-water to give6,7-dichloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(1.4 g).

IR ν_(max) ^(nujol) (cm⁻¹): 3250, 1770, 1720, 1615, 1597

NMR (DMSO-d₆) δ: 2.78 (3H, s), 7.09 (1H, s), 7.29 (1H, s), 9.12 (1H, s),10.18 (1H, s), 11.41 (1H, s)

EXAMPLE 25

3-Methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline(1.5 g) is added to 1,2-dichlorobenzene (30 ml), and the mixture isrefluxed with stirring for 1.5 hour. After cooling, the precipitates aretaken by filtration and recrystallized from dimethylsulfoxide to give3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(0.8 g).

M.p.>280° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3300, 3120, 3080, 1781, 1735, 1680, 1615

MS (m/e): 246 (M⁺)

NMR (DMSO-d₆) δ: 2.80 (3H, s), 6.70-7.50 (4H, m), 9.05 (1H, s), 9.91(1H, s), 11.31 (1H, s)

EXAMPLE 26

d-3-Methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(17.24 g) is suspended in acetic acid (170 ml), and to the suspension isadded dropwise sulfuryl chloride (8.54 ml), and the mixture is stirredat room temperature for 1.25 hour. The reaction mixture is poured intoice-water (500 ml), and the precipitates are taken by filtration. Thecrystals thus obtained are dissolved in ethanol (1 liter), and theundissolved materials are filtered off. The filtrate is treated withactive carbon, and then the solvent is distilled off under reducedpressure. To the residue is added water, and the precipitates are takenby filtration, washed with water, and dried. The procedure is repeatedadditional one time to gived-6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trionemonohydrate [this product has R-configuration at the 4-position of thequinazolinone skeleton] (14 g, yield: 71.3%).

IR ν_(max) ^(nujol) (cm⁻¹): 3650, 3450, 3300, 3220, 3100, 1765, 1730,1660, 1600

NMR (DMSO-d₆) δ: 2.80 (3H, s), 6.92 (1H, d, J=9 Hz), 7.06 (1H, d, J=2Hz), 7.40 (1H, d, d, J=9 Hz, J=2 Hz), 9.11 (1H, s), 10.07 (1H, s), 11.40(1H, s)

[α]_(D) ²⁰ =32.9° (c=1, ethanol)

EXAMPLES 27 to 29

In the same manner as described in Example 26, the correspondingstarting materials are treated to give the compounds as shown in Table4.

                  TABLE 4                                                         ______________________________________                                         ##STR16##                                                                     ##STR17##                                                                    ______________________________________                                        Ex.  Compound (I-a)                                                           No.  R.sup.1                                                                              R.sup.31                                                                             R.sup.41                                                                            R.sup.51                                                                           Physical properties, etc.                       ______________________________________                                        27*.sup.1                                                                          CH.sub.3                                                                             Cl     H     H    Yield: 76.5%; M.p. 169-173° C.;                                        [α].sub.D.sup.20 -33.7°  (c=1,                                   ethanol)                                        28   "      "      "     "    Yield: 71.4%; M.p. >280° C.;                                           IR ν.sub.max.sup.nujol (cm.sup.-1):                                        3300, 1780,                                                                   1740, 1718                                      29*.sup.2                                                                          "      "      CH.sub.3 O                                                                          Cl   M.p. >280° C.;                                                         MS (m/e): 334 (M.sup.+);                                                      IR ν.sub.max.sup.nujol (cm.sup.-1):                                        3200, 1800,                                                                   1715, 1645                                      ______________________________________                                         *.sup.1 This compound is a levorotatory isomer.                               *.sup.2 The NMR spectrum data of this compound: NMR (DMSOd.sub.6) δ     2.79 (3H, s), 3.82 (3H, s), 7.15 (1H, s), 9.10 (1H, s), 9.55 (1H, s),         11.38 (1H, s)                                                            

EXAMPLE 30

3-Methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(1.23 g) is dissolved in acetic acid (50 ml) and thereto are addediodine and sulfuryl chloride (4.0 ml), and the mixture is stirred at 60°C. for 90 hours. After cooling, water (100 ml) is added to the mixture,and the mixture is stirred under ice-cooling. The precipitates are takenby filtration. The crystals thus obtained are dissolved in aqueoussodium hydroxide and the undissolved materials are filtered off. Thefiltrate is neutralized with 10% hydrochloric acid, and the precipitatesare taken by filtration, washed with water and dried to give6,8-dichloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(1.35 g, yield 85.4%).

M. p.>280° C.

IR ν_(max) ^(nujol) (cm⁻¹) 3220, 1799, 1722, 1640

NS (m/e): 314 (M-1), 316 (M+1), 318 (M+3)

NMR (DMSO-d₆) δ: 2.77 (3H, s), 7.06 (1H, d, J=3 Hz), 7.59 (1H, d, J=3Hz), 9.10 (1H, s), 9.53 (1H, s), 11.1-11.7 (1H, br)

EXAMPLE 31

6-Chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(1.4 g) is dissolved in 10.86% (w/w) aqueous sodium hydroxide and thesolution is treated with active carbon and then concentrated underreduced pressure. The residue is crystallized from ethanol and thentaken by filtration. The crystals thus obtained are washed with ethanoland isopropyl ether and dried to give6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione-1'-sodiumsalt (1.17 g, yield 77.3%).

IR ν_(max) ^(nujol) (cm⁻¹) 3330, 3180, 1703, 1648

NMR (DMSO-d₆) δ: 2.62 (3H, s), 6.6-6.9 (2H, m), 7.0-7.5 (2H, m), 9.3-9.8(1H, br)

EXAMPLE 32

In the same manner as described in Example 31, the correspondingstarting material is treated to give the following compound:

(32)d-6-Chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione-1'-sodiumsalt (yield 84.6%).

M.p.>280° C.

[α]_(D) ²⁰ +48.7° (c=1, water)

IR ν_(max) ^(nujol) (cm⁻¹) 3620, 3300, 1708, 1683, 1645, 1600

NMR (DMSO-d₆) δ: 2.63 (3H, s), 6.72 (1H, d, J=10 Hz), 6.76 (1H, d, J=3Hz), 7.13 (1H, d, d, J=10 Hz, J=3 Hz), 7.34 (1H, s), 9.57 (1H, s)

EXAMPLE 33

Isatin (294.3 g) is suspended in tetrahydrofuran (3 liter) and theretoare added with stirring triethylamine (279 ml) and methyl isocyanate(129.8 ml) at 15° C. The mixture is stirred at 20°-25° C. for 2.5 hours(1-methylcarbamoylisatin is produced in the mixture). To the reactionmixture are added 2-ethylisothiourea hydrobromide (444.2 g) andtriethylamine (55.8 ml), and the mixture is refluxed for 2 hours. Aftercooling, the solvent is distilled off under reduced pressure. To theresidue [i.e.3-methyl-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo1,2,3,4-tetrahydroquinazoline]is added 10% hydrochloric acid (4 liter) and the mixture is stirred at70° C. for 4 hours. After cooling, the precipitates are taken byfiltration, washed with water, methanol (1 liter) and chloroform (1liter) in this order and then dried to give3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(369.2 g, yield 75 %).

The physicochemical properties of this product are the same as those ofthe product prepared in Example 21.

EXAMPLE 34

(1)dl-3-Methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(12.3 g) and brucine dihydrate (21.5 g) are dissolved in a mixture (625ml) of methanol and water (3:2 by volume) with heating. After thesolution is allowed to cool, the precipitates are taken by filtration[the filtrate is referred to as "filtrate (I)"]. The crystals thusobtained are recrystallized from a mixture of methanol and water (3:2)to gived-3-methylspiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]2,2'.5'-trionebrucine salt (7.8 g).

[α]_(D) ²⁰ 67.0° (c=1, dimethylformamide)

The salt obtained above (7.8 g) is dissolved in water (20 ml), andthereto is added conc. hydrochloric acid (2 ml). The precipitates aretaken by filtration and recrystallized from a mixture of methanol andwater to gived-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(2.3 g)

M.p. 174-176° C.

[α]_(D) ²⁰ +34.7° (c=1, ethanol)

(2) The filtrate (I) obtained in the above (1) is concentrated intodryness under reduced pressure, and the residue is dissolved in water(60 ml). The solution is neutralized with conc. hydrochloric acid (6ml), and the precipitates are taken by filtration. The filtrate isdistilled under reduced pressure to remove the solvent, and theprecipitates are taken by filtration. The crystals are recrystrallizedfrom a mixture of methanol and water to givel-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(2.1 g).

M.p. 174-176° C.

[α]_(D) ²⁰ 34.7° (c=1, ethanol)

EXAMPLE 35

(1)dl-6-Fluoro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(8.1 g) and quinine (prepared from 16.0 g of quinine hydrochloride) aredissolved in a mixture (450 ml) of methanol and water (2:1 by volume)with heating. After the solution is allowed to cool, the precipitatesare taken by filtration [the filtrate is referred to as "filtrate(II)"]. Thus, there is obtainedd-6-fluoro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trionequinine salt (4.0 g).

[α]_(D) ²⁰ -20.8 ° (c=1, dimethylformamide)

To the salt obtained above (4.0 g) is added 2% hydrochloric acid. Theprecipitates are taken by filtration and recrystallized from a mixtureof methanol and water to gived-6-fluoro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(1.1 g)

M.p. 267° C.

[α]_(D) ²⁰ +37.6° (c=1, ethanol)

(2) The filtrate (II) obtained in the above (1) is regulated to pH 2with 10% hydrochloric acid, and the precipitates are taken byfiltration. The filtrate is neutralized with sodium hydrogen carbonateand extracted with ethyl acetate. The extract is distilled under reducedpressure to remove the solvent, and the residue is neutralized with 2%hydrochloric acid. The precipitates are taken by filtration andrecrystallized from a mixture of methanol and water to givel-6-fluoro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(0.7 g).

M.p. 267° C.

[α]_(D) ²⁰ 39.6° (c=1, ethanol)

EXAMPLE 36

3'-Acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'trione(3.06 g) is dissolved in dimethylformamide (20 ml) and thereto is addedmethyl iodide (1 ml) and further added in portions sodium hydride (60%)(0.3 g) under ice-cooling, and the mixture is stirred at roomtemperature for 30 minutes. To the reaction mixture is added water, andthe mixture is extracted with ethyl acetate. The extract is dried anddistilled to remove the solvent. The residue is purified by silica gelcolumn chromatography (solvent: chloroform) to give3'-acetyl-1'-benzyloxymethyl-1,3-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(3 g, yield: 94.5%) as an oily substance.

IR ν_(max) ^(nujol) (cm⁻¹): 1800, 1720, 1640, 1600

(2) The above product (3.0 g) is dissolved in ethanol (20 ml) andthereto is added palladium black (0.2 g), and the mixture is subjectedto catalytic reduction under hydrogen gas pressure (2-3 atmosphericpressure) for 5 hours. The catalyst is filtered off and the solvent isdistilled off. The residue is dissolved in 10% aqueous sodium carbonate,and the mixture is heated at 60-80° C. for 30 minutes. The reactionmixture is neutralized with 10% hydrochloric acid, and the precipitatesare taken by filtration and recrystallized from dimethylformamide-waterto give3'-acetyl-1,3-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(0.85 g).

M.p. 261-263° C.

MS (m/e): 302 (M⁺)

IR ν_(max) ^(nujol) (cm⁻¹): 1800, 1760, 1715, 1640

NMR (DMSO-d₆) δ: 2.40 (3H, s), 2.80 (3H, s), 3.36 (3H, s), 3.00-4.00(1H, br), 6.90-7.60 (4H, m)

(3) The above product (1.0 g) is added to a sodium ethylate solution[prepared from metallic sodium (161 mg) and ethanol (20 ml)], and themixture is stirred at room temperature for 3 hours. After the solvent isdistilled off, the residue is neutralized with 10% hydrochloric acid,and the mixture is allowed to stand. The precipitates are taken byfiltration and recrystallized from dimethylformamide-water to give1,3-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (500 mg) ascolorless prisms.

M.p. 223-225° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3300, 3200, 1782, 1730, 1630

NMR (DMSO-d₆) δ: 2.86 (3H, s), 3.33 (3H, s), 7.00-7.63 (4H, m), 9.10(1H, s), 11.40 (1H, br)

EXAMPLE 37

In the same manner as described in Example 36-(1),3'-acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trioneand isobutyl iodide are treated to give3'-acetyl-1'-benzyloxymethyl-1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione.

M.p. 70-72° C.

MS (m/e): 464 (M⁺)

NMR (DMSO-d₆) δ: 0.9-1.3 (6H, m), 1.9-2.3 (1H, m), 2.45 (3H, s), 2.84(3H, s), 3.5-4.1 (2H, m), 4.68 (2H, s), 5.16 (2H, s), 6.6-7.1 (3H, m),7.1-7.5 (4H, m)

The above product is treated in the same manner as described in Example36-(2), (3) to give1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione.

M.p. 270° C.

MS (m/e): 302 (M⁺)

IR ν_(max) ^(nujol) (cm⁻¹): 1790, 1723, 1645, 1608

NMR (DMSO-d₆) δ: 0.90 (6H, d, J=7 Hz), 1.8-2.3 (1H, m), 2.79 (3H, s),3.6-4.0 (2H, m), 6.9-7.6 (4H, m), 9.02 (1H, s), 11.19 (1H, s)

EXAMPLE 38

1-Isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(0.76 g) as prepared in Example 37 is suspended in acetic acid (15 ml)and thereto are added sulfuryl chloride (0.3 ml) and a slight amount ofiodine, and the mixture is stirred at room temperature for 19 hours. Thereaction mixture is poured into ice-water, and the precipitates aretaken by filtration and the crystals are dissolved in 10% aqueous sodiumhydroxide. The undissolved materials are filtered off, and the filtrateis neutralized with 10% hydrochloric acid, and the precipitates aretaken by filtration (this dissolution and precipitation procedure isrepeated). The precipitates are taken by filteration and dried to give6-chloro-1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(0.45 g).

M.p. 118° C.

MS (m/e): 338 (M³⁰ +1), 336 (M⁺ -1)

IR ν_(max) ^(nujol) (cm⁻¹): 1790, 1735, 1645, 1602

NMR (DMSO-d₆) δ: 0.90 (6H, d, J=7 Hz), 1.7-2.4 (1H, m), 2.79 (3H, s),3.6-4.0 (2H, m), 7.03 (1H, d, J=3 Hz), 7.10 (1H, d, J=10 Hz), 7.40 (1H,d-d, J=10 Hz, J=3 Hz), 9.09 (1H, s), 11.26 (1H, s)

The preparation of the starting materials is illustrated below.

PREPARATION 1

A mixture of 5-fluoroisatin (9.9 g), triethylamine (1 ml) anddimethylformamide (30 ml) is stirred under ice-cooling, and thereto isadded dropwise methyl isocyanate (3 g) at the same temperature. Themixture is stirred at room temperature for 30 minutes, and theprecipitates are taken by filtration to give5-fluoro-1-methylcarbamoylisatin (8.7 g). M.p. 230°-232° C.

PREPARATIONS 2 to 20

In the same manner as described in Preparation 1, the correspondingstarting materials are treated to give the compounds as shown in Table5.

                  TABLE 5                                                         ______________________________________                                         ##STR18##                                                                     ##STR19##                                                                    ______________________________________                                        [I] (R.sup.1 = CH.sub.3, R.sup.5 = H)                                         Prepn.                                                                              Compound (VII)                                                          No.   R.sup.2                                                                              R.sup.3     R.sup.4                                                                             Physical properties                            ______________________________________                                          2*.sup.1                                                                          H      H           H     M.p. 154-156° C.                         3    "      Cl          "     M.p. 234-236° C.                                                       MS (m/e): 238 (M.sup.+)                         4    Cl     H           "     M.p. 158-160° C.                                                       MS (m/e): 238 (M.sup. +)                        5    H      "           Cl    M.p. 220-222° C.                                                       MS (m/e): 238 (M.sup.+)                         6    "      CH.sub.3 O  H     M.p. 205-208° C.                         7    "      CH.sub.3    "     M.p. 228-230° C.                         8    "      OCH.sub.2 O     M.p. 235-240° C.                           9    "      Cl          Cl    M.p. 220-221° C.                                                       MS (m/e): 272 (M.sup.+)                        10    "      "           CH.sub.3                                                                            M.p. 217-219° C.                        11    "      H           CH.sub.3 O                                                                          M.p. 217-219° C.                        ______________________________________                                        [II] (R.sup.1 = CH.sub.3, R.sup.2 = H)                                        Prepn.                                                                              Compound (VII)                                                          No.   R.sup.3                                                                              R.sup.4     R.sup.5                                                                             Physical properties                            ______________________________________                                        12    H      H           CH.sub.3                                                                            M.p. 192-195° C.                        13    F      F           F     M.p. 169-171° C.                        14    H      H           F     M.p. 145-146° C.                        ______________________________________                                        [III] (R.sup.1 = CH.sub. 3, R.sup.5 = H)                                      Prepn.                                                                              Compound (VII)                                                          No.   R.sup.2                                                                              R.sup.3     R.sup.4                                                                             Physical properties                            ______________________________________                                        15    H      Br          H     M.p. 222-229° C.                        16    CH.sub.3                                                                             H           "     NMR (DMSOd.sub.6) δ:                                                    2.52 (3H, s),                                                                 2.87 (3H, d,                                                                  J=5 Hz), 7.10                                                                 (1H, d,                                                                       J=9 Hz), 7.57 (1H, t,                                                         J=9 Hz), 8.03 (1H, d,                                                         J=9 Hz),                                                                      8.0-8.4 (1H, m)                                17    H      Cl          CH.sub.3 O                                                                          M.p. 202-205° C.                                                       MS (m/e): 211 (M.sup.+)                        18    "      COOC.sub.2 H.sub.5                                                                        H     IR ν.sub.max.sup.nujol (cm.sup.-1):                                        3360, 1748,                                                                   1720, 1703,                                                                   1619                                           19    "      CHCH        "     IR ν.sub.max.sup.nujol (cm.sup.-1):                      COOC.sub.2 H.sub.5                                                                              3360, 1757                                                                    1738, 1705,                                                                   1640, 1617                                     ______________________________________                                        [VI] (R.sup.2 -R.sup.5 = H)                                                   Prepn.                                                                              Compound (VII)                                                          No.   R.sup.1            Physical properties                                  ______________________________________                                        20    CH.sub.3 (CH.sub.2).sub.3                                                                        M.p. 97-99° C.                                21                                                                                   ##STR20##         M.p. 189-190° C.                              22                                                                                   ##STR21##         IR ν.sub.max.sup.nujol (cm.sup.-1): 3300,                                  1755, 1740, 1708                                     ______________________________________                                         *.sup.1 This compound is the same as the compound disclosed in Ann. Chem.     1974, page 2003.                                                         

PREPARATION 23 1-Methylcarbamoylisatin (8.16 g) is dissolved intetrahydrofuran (100 ml), and thereto is added 2-ethylisothioureahydrobromide (7.4 g), and the mixture is stirred at room temperature for3 hours. The precipitates are taken by filtration, washed with water anddried to give3-methyl-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline(8.0 g). M.p.>280° C. PREPARATIONS 24 to 25

In the same manner as described in Preparation 23, the correspondingstarting materials are treated to give the following compounds.

(24)3-(4-Methylphenyl)-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline,M.p. 215°-218° C. (recrystallized from dimethylformamide-water)

(25)3-(4-Chlorophenyl)-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline,M.p. 223-224° C.

PREPARATION 26

1-Methylcarbamoylisatin (10.2 g) and 1,8-diazabicyclo[5.4.0]-7-undecene(0.3 g) are dissolved in tetrahydrofuran (100 ml), and thereto is addedurea (4.5 g), and the mixture is refluxed for 10 hours. After cooling,the precipitates are taken by filtration, washed with water and methanoland recrystallized from a mixture of dimethylsulfoxide and ethanol togive3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline,M.p.>280° C.,

MS (m/e): 246 (M⁺ -18)

PREPARATION 27

(1)3-Methyl-spiro[1,2,3,4-tetrahydroquinazolidine-4,4'-imidazolidine]-2,2',5'-trione(7.38 g) is dissolved in dimethylformamide (60 ml), and thereto is addedsodium hydride (60%) (1.2 g) at 15° C., and the mixture is stirred atroom temperature for 30 minutes. To the mixture is added benzyloxymethylchloride (4.71 g) at room temperature, and the mixture is furtherstirred at room temperature for 30 minutes. To the mixture is addedwater, and the mixture is extracted with ethyl acetate. The organiclayer is washed with water, dried and then distilled to remove thesolvent. The residue is crystallized from dimethylformamide-water togive 1'-benzyloxymethyl-3-methylspiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2'.5'-trione (10.4g).

M.p. 226-227° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3200, 3050, 1800, 1735, 1660

(2) The product obtained above and acetyl chloride are treated in thesame manner as described above (except that there is usedisopropanol-isopropyl ether as a solvent for crystallization) to give3'-acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione(yield: 70%) M.p. 209-211° C.

What is claimed is:
 1. A quinazolinone compound of the formula:##STR22## wherein R is hydrogen atom or lower alkyl, R¹ is a loweralkyl, and R², R³, R⁴ and R⁵ are the same or different and are eachhydrogen atom, a halogen atom, a lower alkyl or a lower alkoxy, or asalt thereof.
 2. The compound as claimed in claim 1, wherein R ishydrogen of C₁₋₄ alkyl; R¹ is C₁₋₄ alkyl; and R², R³, R⁴ and R⁵ are thesame or different and are each hydrogen, halogen or C₁₋₄ alkyl.
 3. Thecompound as claimed in claim 1, wherein R is hydrogen or C₁₋₄ alkyl; R¹is C₁₋₄ alkyl; R² is hydrogen; R³ is halogen; R⁴ is hydrogen, halogen ofC₁₋₄ alkyl; and R⁵ is hydrogen or halogen.
 4. The compound as claimed inclaim 3, wherein R is hydrogen or isobutyl; R¹ is methyl; R² ishydrogen; R³ is fluorine, chlorine or bromine; R⁴ is hydrogen, chlorineor methyl; and R⁵ is hydrogen of chlorine.
 5. The compound as claimed,in claim 4, which is6-chloro-3-methyl-spiro-[1,2,3,4-tetrahydroquinazoline-4,4'-imidaxolidine]-2,2',5'-trioneor a salt thereof.
 6. The compound as claimed in claim 4, which isd-6-chloro-3-methyl-spiro-[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trioneor a salt thereof.
 7. An optically active isomer of the compound as setforth in claim
 1. 8. The compound as claimed in claim 7, which is adextro-rotatory isomer.
 9. A pharmaceutical composition which comprisesan effective amount of the compound as set forth in claim 1 in admixturewith a conventional pharmaceutically acceptable carrier or diluent. 10.A method for treatment of diabetic complications in a warm-bloodedanimal which comprises administering to said warm-blooded animal aneffective amount of the compound as set forth in claim 1.